Phenylalkane derivatives in the treatment of inflammation

ABSTRACT

1. A METHOD FOR RELIEF OF AN INFLAMMATORY CONDITION WHICH METHOD COMPRISES ADMINISTERING TO A SUBJECT HAVING SUCH CONDITION F THERAPEUTICALLY EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA:   1-(2-R7,R8,(H3C)N-PHENYL(B)-O-),2-(HOOC-CH2-),4-R6-   BENZENE(A)   WHEREIN R6 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGE AND METHYL; R7 IS SELECTED FROM THE GROUP CONSISTING OF CHLORINE BROMINE AND METHOXY, PROVIDED THAT R7 IS METHOXY ONLY WHEN R8 IS SELECTED FROM THE GROUP CONSISTING OF CHLORINE AT POSITION 4 AND BROMINE AT POSITION 4; R3 IS SELECTED FROM THE GROUP CONSISTING OF CHLORINE AT POSITION 4, BROMINE AT POSITION 4, CHLORINE AT POSITION 5, BROMINE AT POSITION 5, ALKYL OR 1 TO 6 CARBON ATOMS AT POSITOON 4, TRIFLUOROMETHYL AT POSITION 6 AND METHYL AND AT POSITION 6. AND N IS 0, 1 OR 2.

United States Patent US. Cl. 424-317 16 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula:

4 e 3' R R B 2 A F W i (EHRCOOH which have from 2 to 4 substituents in the B ring wherein R, R R R R and R represent certain specified substituent groups and p is selected from O, 1 and 2. The compounds of the invention possess anti-inflammatory activity.

This application is a division of application Ser. No. 132,891, filed Apr. 9, 1971, now issued as U.S. Pat. No. 3,766,263 on Oct. 16, 1973.

This invention relates to phenylakane derivatives and to processes for their production. The invention also relates to therapeutic compositions comprising as the active ingredient one or more of these phenylalkane derivatives.

Acetyl salicylic acid (aspirin) has been in use for over 50 years for the relief of pain and the alleviation of inflammatory states. In the late 1950s there was much interest in the discovery that stomach ulcertation and gastrointestinal bleeding could occur in patients taking aspirin, particularly those patients suffering from various inflammatory states such as rheumatoid arthritis, osteoarthritis, rheumatic fever and ankylosing spondylitis in which the treatment necessitated continued high dosages of the drug. Arylacetic acids have been investigated extensively for anti-inflammatory activity, and thus Work has led to the introduction of Ibuprofen, .for example. This drug in common with other drugs such as Phenylbutazone and aspirin, is strongly ulcerongenic in animals such as rats. We have now prepared novel arylacetic acid derivatives, in particular ortho phenoxy phenylacetic acid derivatives, which possess anti-inflammatory activity, and certain of which possess to a minimal extent only the ulcerogenic side effects encountered with known antiin-flamrnatory drugs.

According to the present invention there are provided compounds of the formula:

which are di-, trior tetrasubstituted in the B ring, and wherein R is hydrogen or methyl; R is hydrogen, methyl or chlorine; R is alkyl of from 1 to 4 carbon atoms or chlorine;

3,845,215 Patented Oct. 29, 1974 R is alkyl of from 1 to 6 carbon atoms at position 4, triflu-oromethyl at position 5, or hydrogen or chlorine;

R is hydrogen or chlorine;

R is alkyl of from 1 to 4 carbon atoms and p is 0 or 1,

or p may be 2 when R is methyl;

and When R is alkyl of from 1 to 6 carbon atoms at position 4, R may be hydrogen and in this case R is chlorine or trifiuoromethyl at position 3 and p is 1;

provided that the B ring does not have two alkyl groups containing more than one carbon atom in adjacent positions and that in a compound with alkyl substituents at positions 2 and 6 of the B ring at least one of these alkyl substituents is methyl or ethyl;

and also provided that the compound does not have more than 3 chlorine substitutents.

Additionally, when R is 'alkyl of from 1 to 6 carbon atom-s at position 4 or chlorine then R may also represent alkoxy of from 1 to 4 carbon atoms or hydroXy;

R .may also represent alkyl of from 7 to 18 carbon atoms at position 4 when R is chlorine and there are no other substitutents in the B ring;

R may also represent alkoxy of from 1 to 4 carbon atoms or hydroxy when R is chlorine; and one or more chlorine substituents in the compound may be replaced by bromine.

By di-, triand tetra-substituted we mean that there are two, three or four substituents in the B ring in addition to the ether linkage.

In a preferred aspect of the invention there are provided compounds of the formula:

R is hydrogen or methyl;

R is chlorine;

R is chlorine at positions 4 or 5, alkyl of from 1 to 6 carbon atoms at position 4, tr-ifiuromethy-l at position 5 or methyl at position 6;

and n is 0, 1 or 2. Additionally when R is chlorine at position 4, R may also represent a methoxy group; and one or more chlorine substitutents in the molecule may be replaced by bromine.

In a particularly preferred aspect the present invention provides 2-chloro4-alkyl(C to C phenoxyphenyl acetic acids which may be optionally substituted by methyl at position 5' of Ring A and 2,4-dichlorosubstituted phenoxyphenylacetic acids which may be optionally substituted by one or two methyls in Ring B and methyl at position 5 of Ring A.

The invention also provides therapeutic compositions comprising as active ingredients one or more compounds of Formula I or Formula II in association witha phari ti-i ceutically inactive diluent or carrier.

The compounds and compositions of the present invention have anti-inflammatory and 'analgesic"properti'es.'-

The compounds of Formula I in which R is hydrogen may be prepared by reacting together compounds of Formulae III and IV.

R R; l C O CH:

R III IV 3 in which R R R and R and R and p are as hereinbefore defined with reference to Formula I, except that neither R nor R may represent a hydroxy group, Y is ONa or OK and X is chlorine, bromine or iodine, at a temperature of a least 120 C. in the persence of a copper catalyst to produce a compound of Formula V 1 2 430 CH: V

which is thereafter transformed into a compound of Formula I in which R is hydrogen by treatment with sulphur and morpholine to form a thioacetmorpholide of Formula VI which is then hydrolysed.

The copper catalyst used in the above reaction is preferably copper in finely divided form.

The hydrolysis of the thioacetmorpholide is convenient- 1y carried out under basic conditions, but where there is a trifluoromethyl substituent in the molecule acidic conditions may be necessary, for example it has been found that 2-(chloro-S-trifluoromethylphenoxy)-5-methylphenylacetic acid must be hydrolysed under acidic conditions.

The compounds in which either R or R represent hydroxy may be prepared by O-demethylation of the analogous methoxy compounds, for example by treatment with glacial acetic acid and hydriodic acid.

Compounds of Formula I in which R is methyl may be prepared from the compounds of Formula I in which R is hydrogen by the following route:

C O Et C00 (0 Etz) I ArCHzCOOH ArCHzCOOEt OEt r C O 0E1; l MeI NaOEt .ArCHMe (0 021302 .AJ'CHMeCOOH ArCHMe(COzH)2 The compounds of Formulae III and IV when not commercially available may be prepared by standard techniques.

The invention is further illustrated by the following non-limiting examples:

EXAMPLE 1 2- 2,4-Dichloro-S-Methylphenoxy) --Chlorophenylacetic Acid A mixture of 2,5-dichloroacetophenone (37.8 g., 0.2 mole), sodium 2,4-dichloro-5-methylphenoxide (79.6 g., 0.4 mole), 2,4-dichloro-5-methylphenol (35.4 g., 0.2 mole) and a copper catalyst (1.0 g., prepared according to R. Q. Brewster and T. Groening Organic Syntheses, John Wiley & Sons, Inc, New York, 1943, C011. Vol. 11, p. 446) was stirred under an atmosphere of nitrogen at an internal temperature of 120-125 for about 24 hours. The mixture was cooled, diluted with water and extracted three times with ether. The combined extracts were washed free of 2,4-dichloro-S-methylphenol with dilute sodium hydroxide solution, and then washed with water and dried. The ether was evaporated and the I residue was distilled. The product (30 g., 45%) was col- 4 lected at 168174/0.25 mm. and solidified on being cooled. A sample was crystallised from methanol to give 2-(2,4-dichloro S-methylphenoxy) 5-chloroacetophenone, m.p. 7374.5 C.

Analysis.Calcd. for C H Cl O C, 54.7; H, 3.4; CI, 32.3. Found: C, 54.55; H, 3.35; Cl, 32.6%.

2-(2,4-Dichloro 5 methylphenoxy)-5-chloroacetophenone (18.0 g., 0.055 mole), morpholine (17.1 g., 0.197 mole) and sulphur (4.6 g., 0.143 mole) were heated under gentle reflux for 24 hours. The warmmixture was poured into methanol (85 ml.) and left to cool in an ice bath. The yellow crystals which formed (17.5 g., were filtered off. A portion was crystallised from methanol, giving 2-(2,4-dichloro-S-methylphenoxy)-5- chlorophenylthioacetmorpholide as pale yellow needles, m.p. 135.5137 C.

Analysis.Calcd. for C H Cl NO S: C, 53.0; H, 4.2; Cl, 24.7; N, 3.25; S, 7.4. Found: C, 53.0; H, 4.3; CI, 24.5; N, 3.2; S, 7.2%.

2-(2,4-Dichloro 5 methylphenoxy)-5-chlorophenylthioacetmorpholide (14.0 g., 0.32 mole), potassium hydroxide (14.0 g.) and methanol (140 ml.) were heated under reflux for at least 48 hours (72 hours). The mixture was evaporated, water was added and the mixture Was extracted with ether. The aqueous layer was then acidified with concentrated hydrochloric acid and the product was extracted into ether. The ether extracts were washed with water, dried and evaporated. The solid residue (10.5 g., 93%) was crystallised from light petroleum (b.p. 100) to give 2-(2,4-dichloro-5-methylphenoxy)-5-chlorophenylacetic acid as colourless needles, m.p. 145148 C.

Analysis.-Calcd. for C H Cl O C, 52.1; H, 3.2; CI, 30.8. Found: C, 52.1; H, 3.25; Cl, 30.2%.

The overall yield of acid from 2,5-dichloroacetophenone is 32%.

EXAMPLE 2 2- (2-Chloro-4-Methylphenoxy) -5-Methylphenylacetic Acid p-Chlorotoluene was acetylated with acetyl chloride in the presence of aluminium chloride by the method of A. F. Dokukina, et al., Zhur. obshchei Khim, 1956, 26, 1651 (Chem. Abs. 1957, 51 1886a). The product was a mixture containing about 70% of the desired 2-chloro- S-methylacetophenone and 30% of the isomeric S-chloro- Z-methylacetophenone, and was used without separation of the isomers. This is satisfactory, since the minor component contains an unactivated chlorine atom (in contrast to the major component, the chlorine atom of which is activated by the orthoacetyl group) and is recovered unchanged after reaction of the mixture with a phenoxide.

The chloromethylacetophenone mixture described above (33.7 g., 0.2 mole) sodium 2-chloro-4-methylphenoxide (66.0 g.; 0.4 mole), 2-chloro-4-methylphenol (14.25 g., 0.1 mole) and copper catalyst (1.0 g. prepared as in Example 1 above) were stirred in a nitrogen atmosphere for about 24 hours at an internal temperature of The reaction mixture was worked up as in Example 1. Distillation of the crude product in vacuo afforded 11.2 g. of forerun, b.p. 60137 C./0.3 mm. (consisting largely of 5-chloro-2-methylacetophenone), followed by the desired 2-(2-chloro-4-methylphenoxy)-4-methylacetophenone (27.3 g., 71% yield based on amount of 2- chloro-5-methylacetophenone present in the original mixture) b.p. 137-143 C./0.3 mm.

Analysis.Calcd. for C H ClO C, 70.0; H, 5.5; Cl, 12.9. Found: C, 69.9; H, 5.8; Cl, 12.7%.

2-(2-Chloro 4 methylphenoxy) 5 methylacetophenone (146 g., 0.53 mole) was heated with sulphur and morpholine as in Example 1. On pouring the reaction mixture into methanol there was obtained g. (85%) of yellow solid. Crystallisation from methanol afforded 2-(2 chloro 4 methylphenoxy)-5-methylphenylthio. acetomorpholide m. p. 99102 C. i J

Analysis.-Calcd. for C H ClNO S: C, 63.9; H, 5.9;

Cl, 9.4; N, 3.7; S, 8.5. Found: C, 63.9; H, 5.8; CI, 9.7;

2-(2-chloro-4-methylphen0xy) 5 methylphenylthioacetmorpholide (22 g., 0.059 mole) was hydrolysed as in Example 1. The crude product (14 g.) was an oily solid, which was crystallised from carbon tetrachloride to give g. (58%) of material of m.p. 88-93 C. A sample rccrystallised from light petroleum (b.p. 60-80" C.) gave 2-(2-chloro-4-methylphenoxy)-5-methylphenylacetic acid as colourless needles, m.p. 9597.

AnaIysis.Calcd. for C H ClO C, 66.1; H, 5.2; C1, 12.2. Found: C, 66.25; H, 5.25; Cl, 12.4%.

EXAMPLE 3 2-[2-(2,4-Dichlorophenoxy) phenyl] propionic acid A solution of sodium (2.4 g.; 0.088 mole) in ethanol (48 ml.) was added over 3 hours to a solution stirred at 140 C. of ethyl -2-(2,4-dichlorophenoxy) phenylacetate (26.0 g.; 0.08 mole) in diethyl carbonate (22 ml.). The ethanol was removed by distillation through a 12 cm. column packed with glass helices. The last traces of ethanol from the reaction were removed by slow distillation for 4 hours at a head temperature of 127 C.

After cooling the solution was poured in conc. hydrochloric acid (400 ml.) and ice (400 g.). Water (400 ml.) was added and the product was extracted with ether. The ether extracts after washing with water, drying with magnesium sulphate, were evaporated, and the residual oil distilled, diethyl 2-(2,4-dichlorophenoxy) phenylmalonate (23 g.) Was collected at 177-178 C./0.25 mm.

A solution of sodium (1.15 g.; 0.05 mole) in ethanol (100 ml.) was added to a solution of the malonate (19.9 g.; 0.05 mole) in ethanol (40 ml.), followed by the addition of methyl iodide (15.6 ml.; 0.25 mole). After heating under reflux for 1 hour additional methyl iodide (4 ml.) was added, and heating continued for 1% hours. The solution was evaporated. Water was added, and the product extracted with ether. The ether extracts after washing with aqueous sodium bisulphite and water, drying with magnesium sulphate, were evaporated to give the methylated malonic ester as an oil (18.6 g.), which was not purified further.

A mixture of the methylated malonic ester (6 6 g.), water ml.), ethanol (24 ml.) and sodium hydroxide (3.0 g.) was heated under reflux with stirring for 3 hours. The solution was diluted with water, acidified with hydrochloric acid and the product extracted into ether. The ether extracts, after drying with magnesium sulphate, were evaporated to give the methylated malonic acid as an oil (6.4 g.), which was not purified further.

The methylated malonic acid (6.4 g.) was decarboxylated by heating at 180 C. for 1 hour and then at 200 C. for 1 hour. The product was crystallised twice from n-hexane to give 2.1 g. of 2-[2-(2,4-dichlorophenoxy) phenyl] propionic acid, m.p. 101-103" C.

Analysis.Calcd. for C H Cl O C, 57.9; H, 3.9; Cl, 22.8. Found: C, 58.3; H, 4.0; C1, 22.2%.

EXAMPLE 4 2- (2-chloro-4-n-propylphenoxy) -5-methylphenylacetic acid A solution of 2-chloro-4-n-propylphenol (49.5 g., 0.29 mole) in methanol (200 ml.) was treated with sodium methoxide in methanol (62.6 ml. of 24% w./v. solution, 0.28 mole). The solution was evaporated in vacuo to give the corresponding phenoxide containing a slight excess of the phenol. This was then allowed to react with the mixture of 2-chloro-S-methylacetophenone and its isomer (94.5 g., 0.56 mole) in the presence of copper as in Example 2. 2-(2-Chloro-4-n-propylphenoxy)-5-methylacetophenone was collected at 155-160 C. at 0.35 mm. (66.1 g., 75%).

Analysis.- Calcd. for C H ClO C, 71.3; H, 6.3; Cl, 11.7. Found: C, 71.4; H, 6.3; Cl, 11.7%.

2-(2-Chloro 4 n propylphenoxy)-5-methylacetophenone (30.3 g., 0.1 mole) was heated with morpholine and sulphur as in Example 1. The yield of 2-(2-chloro-4- n-propylphenoxy) 5 methylphenylthioacetmorpholide was 28.2 g. (70%); m.p. 8989.5 C. from methanol.

Analysis.Calcd. for C H ClNO S: C, 65.4; H, 6.5; Cl, 8.8; N, 3.8; S, 7.9. Found: C, 65.3; H, 6.5; Cl, 8.9; N, 3.5; S, 8.0%.

A mixture of 2-(2-Chloro 4 n propylphenoxy)-5- methylphenylthioacetmorpholide (25 g., 0.062 mole) and potassium hydroxide (50 g.) in methanol (250 ml.) was heated under reflux for 48 hours. The product was worked up as in Example 1 to give 2-(2-chloro-4-n-propylphe noxy)-5-methylphenylacetic acid (16.1 g., 82%), m.p. 8586 C. from light petroleum (b.p. 6080 C.).

Analysis.-Calcd. for C H ClO C, 67.8; H, 6.0; Cl, 11.1. Found: C, 68.1; H, 6.2; Cl, 11.2%.

EXAMPLE 5 2- 2-Chloro-5-trifluoromethylphenoxy) -5- methylphenylacetic acid A mixture of 2-(2-chloro-S-trifluoromethylphenoxy)- S-methylacetophenone (prepared by the method of Example 4, 15.0 g., 0.045 mole), sulphur (3.8 g., 0.118 mole) and morpholine (14.3 g., 0.165 mole) was heated under reflux for 4 hours. It was then Worked up as in Example 1 to give 15.95 g. (83%) of product, m.p. 120- 124 C. A portion was crystallised twice from methanol to give 2 (2-chloro-5-trifluoromethylphenoxy)-5-methylphenylthioacetmorpholide as pale yellow needles, m.p. 128129 C.

Analysis.-Calcd. for C H ClF NO S: C, 55.9; H, 4.45; Cl, 8.2; F, 13.25; N, 3.3; S, 7.5. Found: C, 55.6; H, 4.4; CI, 8.1; F, 13.6; N, 3.4; S, 7.8%.

A mixture of 2- (2-ch1oro-5-trifluoromethylphenoxy)- 5-methylphenylthioacetmorpholide (9.0 g., 0.021 mole), acetic acid (60 ml.), concentrated sulphuric acid (9 ml.) and water (13 ml.) was heated under reflux for 24 hours. The solution was filtered hot from a residue of sulphur. Some product crystallised in the cold filtrate and the remainder was isolated by diluting the filtrate with water. The combined solids (6.85 g.) of melting point about 120 C., were crystallised from light petroleum (b.p. 80- C.) to give 5.5 g. (76%) of 2-(2-chloro-5-trifluoromethylphenoxy)-5-methylphenylacetic acid as pale pinkish microcrystals, m.p. 123-124 C.

Analysisr calcd. for C H ClF O C, 55.7; H, 3.52 Cl, 10.3; F, 16.5. Found: C, 55.8; H, 3.5; Cl, 10.1; F, 16.6%.

EXAMPLE 6 2- 2-chloro-4-n-pentylphenoxy) -5- methylphenylacetic Acid The crude acid obtained in 52% yield when 2-chloro- 5-n-pentylphenol was allowed to react as in Example 4 (footnotes r and u of the table apply) was an oil which could not be crystallised. It was therefore purified via its amide. The oily acid (29.4 g., 0.085 mole) was dissolved in methylene chloride (50 m1.), thionyl chloride (6.9 ml., 0.095 mole) was added, and the solution was heated under reflux for 2 hours. Volatile material was distilled in vacuo, and two portions of dry benzene were added and similarly removed in vacuo. The crude acid chloride was taken up in dry benzene (100 ml.) and added dropwise with stirring to ammonia (d=0.880, 300 ml.). The resulting suspension was shaken with ether and filtered from undissolved product. The organic layer was separated from the filtrate, washed with water, dried over magnesium sulphate and evaporated. The solid residue was combined with the material obtained by filtration and triturated several times with ether and then crystallised from methanol to give 11.4 g. of 2-(2-chloro-4-npentylphenoxy) 5 methylphenylacetamide, m.p. 136- 137.5 C. This was heated under reflux with 20% methanolic potassium hydroxide ml.). The solution was filtered, the filtrate was evaporated to dryness and the residue was taken up in water. The solution was acidified with hydrochloric acid and extracted with ether. The extract was washed with Water, dried over magnesium sulphate and evaporated to dryness. The residual oil and then with water, dried over magnesium sulphate, and evaporated to give a yellow oil. This was crystallised from light petroleum (b.p. 6080 C.) to give 1.9 g. (87%) of 2 (4 chloro 2-hydroxyphenoxy)-5-methylphenylacetic acid, m.p. 116-117 C.

solidified when triturated with light petroleum (b.p. 60'- Analyszs.-Calcd. for C I-1 C104; C, 61.8; H, 4.5; Cl, 80 C.). crystallisation from this solvent afforded 2-(2- 12.1. Found: C, 61.8; H, 4.5; Cl, 11.9%. chloro- 4 n pentylphenoxy) S-methylphenylacetrc The table sets out details of further examples of orthoacid, m.p. 75-77"; yield 6.7 g. (23% recovery from crude phenoxyphenylacetlc acid derlvatlves which may be subacid 12% overall yield). stituted at position 5 of the A ring and at positions 2, 3,

Analysls.Calcd. for C H CIO C, 69.2; H, 6.7; Cl, 4, 5 or 6 of the B r1ng WhlCh were prepared by the pro- 10.2. Found: C, 69.3; H, 6.6; CI, 10.3%. cedures Of the above examples.

. TABLE I Substituent on Percent calc. Percent iound Yield, Crystn. Method percent M.P., C. solvent Formula C H 01 C H Cl 11 1 37 134-13 0011 0111111101101 566 3.4 23.9 56.6 3.1 23.6 1 25 118-120 0011 0111111101101 56.6 3.4 23.9 56.6 3.3 23.5 1 19 ,119-121 0011 011111101101 56.6 3.4 23.9 56.6 3.2 23.8 11 1 3 152.5-154 0011; 011111 0111111101101 56.6 3.4 23.9 56.6 3.2 23.8 1 35 114.5-116 0011 0111111101101 56.6 3.4 23.9 56.2 3.4 23.4 b 1 19 149-150 0011 01111110101 65.1 4.7 12.8 64.9 4.7 13.1 b 1 20 104-107 0011 01111110101 65.1 4.7 12.8 64.9 4.7 12.9 1 29 131-133 C014 C15H12Cl209 57.9 3.9 22.8 57.7 3.7 22.9 1 22 159-162 0011 011111101101 59.1 4.3 21.8 59.3 4.1 21.5 1 13 106-108 Cyclohexane 011H101101 50.7 2.7 32.1 50.9 2.8 31.5 1 139-141 M11011 011H101101 50.7 2.7 32.1 50.6 2.7 32.2 1 33 91-925 L.P. 80-100 011H1101101 57.9 3.9 22.8 57.7 4.0 22.8 1 32 94-96 L.P. 80-100 011H110l101 57.9 3.9 22.8 58.1 3.95 22.65 1 134-1355 L;P.80100 011H1101101 59.1 4.3 21.8 59.2 4.4 22.2 l 23 168-169 0011 0111111101101 534 3.6 29.6 53.2 3.6 29.2 n 2 33 153. 5-155 01H1 011111101101 57.9 5.9 22.8 57.9 3.9 23.1 2 30 96.5-97.5 L.P. 60-80 01111110101 66.1 5.2 12.2 65.7 5.0 12.3 2 27 147-149 Et011/1110 011111101101 59.1 4.3 21.8 59.2 4.5 21.6 2 18 133-134 L.1 -60 011H1101101 59.1 4.3 21.8 59.5 4.6 21.9 2 24 97.5-100 L.P. -80 01111110101 67.0 5.6 11.6 66.7 5. 11.5 2 30 153-154 L.P. 60-80 011H1101101 60.2 4.8 20.9 60.2 4.8 21.0 d 2 30 127-128 0011 011111101101 57.9 3.9 22.8 57.8 4.1 22.8 2 23 120-121 0011 C11H1101101 57.9 3.9 22.8 57.8 3.9 23.3 2 17 135-136 0011 01111110101 66.1 5.2 12.2 66.0 5.15 12.5 1: v u 2 12 130. 5-131.5 001.1 011H110l101 57.9 3.9 22.8 58.1 3.8 22.4 2 25 135-136 L.P.60- 011H110101 67.0 5.6 11.6 66.9 5.8 11.8 1 22 146-148 MeOH/H1O ciiHio rzoa 43. 55 2.6 41.4 43.7 2.6 41.5 b r u 2 29 125-1265 0011 0111111101 76.3 6.8 76.1 7. 0 a r u 2 34 1 157. 5-159 5 0011 01111110101 66.1 5.2 12.2 66.1 5.5 12.2 d 2 45 118-120 001 011111101101 57.9 3.9 22.8 57.4 3.8 22.5 f u 2 27 114-117 Hexane 01111110101 67.0 5.6 11.6 66.6 5.5 11.9 H u w 2 6 62-64 L.P. 30 10" 0111111101 76.5 7.4 76.5 7.6

1n 2 25 112-113 L.P.60-80 011H110101 66.1 5.2 12.2 65.8 5.3 12.2 f r u 2 25 114-114 5 L.P.6081') 01111110101 67. 0 5.6 11.6 67.2 5.9 11.9 H .2 17 104. 5-106 L.P. 60-80 011111110101 68.6 6.4 10.65 68.5 6.2 10.7 1 15 117-119 L.P.60-80 01111110101 66.1 5.2 12.2 66.1 5.2 12.1 f 2 34 106-1075 L.P. 60-80 01111110101 57.0 5.6 11.6 67.3 5.9 11.3 1 r 4 31 100-101 Hexane 011111110101 67.8 6.0 11.1 67.5 5.9 11.3 4 23 70-71.5 L.P. 60-80 0111-1110101 68.6 6.4 10. 65 68.1 6.4 10.8 4 20 85-86 L.P.80- 01111110101 68.6 6.4 10. 65 68.5 6.4 10.5 4 15 53-54 Hexane 011111110101 68.6 6.4 10. 65 68.35 6.3 10. 9 1 u 2 25 133-134 L.P. 80100 011H110101 68.6 6.4 10. 65 68.7 6. 0 10.9 4 40 71-73 P. 60-80 01111110101 69.9 7.0 9.8 69.8 7.1 9.9 4 38 61-63 MeOH/HzO 011111110101 71.0 7.5 9.1 70.9 7.6 9.1 4 20 60-61 M11011/1110 01111110101 71.5 7.75 8.8 71.4 7.8 8.7 k 1 30 58-60 eOH 01111110101 72.0 8.0 8.5 72.3 8.2 8.7 k 4 32 58-61 M11011 01111150101 72.5 8.2 8.2 72.1 8.3 8.3 4 27 56-58 M1011 01111110101 72.85 8.4 8.0 72.8 8.4 8.1 c 2 12 104-1055 0011 01111110101 62.7 4.9 11.6 62.7 5.0 11.8

1 Bromine.

Ketone:phenoxide:phenol in ratio 224:1.

b Ketone:phenoxidezphenol in ratio 1:

v Ketonezphenoxidezphenol in ratio 1:

d Ketonezphenoxidezphenol in ratio 2:

Ketone: phenoxide: phenol in ratio 4:6:

f Ketone:phenoxidezphenol in ratio 4: 2:1.

8 Ketonezphenoxidezphenol in ratio 2:1:1.

h The phenoxide-phenol mixture was prepared using the proportions and method of Example 4. The subsequent procedure was that of Example 1, using 2 molar proportions of o-chloroacetophenone to 1 molar proportion of phenoxide.

Ketonezphenoxidezphenol in ratio 3:1:0.

Ketone:phenoxide:phenol in ratio 521:0.

111 Large excess of the phenol required to solubihse the reaction mixture.

Phenoxide condensation carried out at EXAMPLE 7 2-(4-chloro-2-hydroxyphenoxy)-5-methylphenylacetic Acid A mixture of 2 (4 chloro-Z-rnethoxyphenoxy)-5- methylphenylacetic acid (2.3 g., 0.0075 mole), glacial acetic acid (16.2 ml.) and hydriodic acid (4.4 ml.) was heated under reflux for 2 hours. Material of b.p. below 100 was removed by distillation and heating under reflux was continued for a further 20 hours. The solution was poured into water (200 ml.) and extracted with ether. The extract was washed with aqueous sodium thiosulphate D Phenoxide condensation carried out at fi The aryloxyketone crystallised directly without having to be distilled rst r The thiomorpholide was not obtained as a solid when the hot reaction mixture was poured into methanol. The methanol was evaporated and the residue was dissolved in ether. The solution was washed with dilute hydrochloric acid to remove morpholine, then with water, dried over magnesium sulphate and evaporated. The residual oil was then hydrolysed by the procedure used for solid thiomorpholides.

B Thiomorpholide hydrolysed for 24 hours only.

1 Thiomorpholide hydrolysed in a mixture of 30 g. potassium hydroxide and 20 ml. of Z-ethoxyethanol.

t 20% potassium hydroxide in methanol was used for the hydrolysis 8 age.

w The crude acid was purified via its amide as in Example 6.

No'rE.-L.P. refers to light petroleum of the given b.p. range.

Screening for anti-inflammatory activity has been carried out employing the established adjuvant arthritis test, based on a procedure described by Newbould (Brit. J. Pharmacol, 35, 487 (1969). The following is a brief description of the method which we use:

On day 0 of the test 0.05 ml. of liquid paraffin containing 5 mg./ml. of dead Mycobacterium tuberculosis is injected into the plantar surface of the left hind paws of male rats. On day 21 the animals are weighed and the arthritis assessed by measurement of the volume of the left hind (injected) paw. Those animals in which the arthritis has not fully developed are rejected and the remainder divided into groups so that the mean left hind paw volume of each group is approximately the same. The rats are then dosed orally with the drug under test on days 21 to 27 inclusive. The control animals receive the same dose volume (10 ml./kg.) of the drug vehicle, acacia. On day 28 (approximately 24 hours after the final dose) the animals are weighed and the left hind paw volume measured. The results are expressed as the percentage change in paw volume and body weight following drug treatment.

Antipyretic activity has been assessed in yeast-fevered rats using a modification of the method of Winder et al. (I. Pharmac. exp. therap, 133, 117 (1961)).

Screening to determine the extent of gastric ulceration following acute administration of a drug in rats has been carried out by a procedure based on that of Martindale et al. (J. Pharm, Pharmacol, 12, 153T-158T (1960)). U1- ceration was assessed at 4 hours in the case of Phenylbutazone and Ibuprofen, but at 24 hours in the case of the compounds of the invention, for which preliminary studies indicated a greater ulcerogenic effect at 24 hours than at shorter time intervals. Acetylsalicylic acid was used as a positive control for the 24 hour studies.

Table II below sets out results We have obtained on a number of compounds. Calculation of the ratio of the approximate minimum ulcerogenic dose (MUD) to the corresponding approximate daily minimum effective (antiarthritic) dose (MED) clearly demonstrates the reduced ulcerogenic potential of our compounds relative to their therapeutic activity when compared with established antiinfiammatory agents.

The unsubstituted analogue, o-phenoxyphenylacetic acid,

is devoid of anti-inflammatory activity and produces no ulceration after six hours and only slight ulceration 24 hours after administration of 1 g./kg. Moreover, with mphenoxyphenylacetic acid (no anti-arthritic activity) there was ulceration 4 hours after administration of 100 mg./ kg, with p-phenoxyphenyiacetic acid ulceration 4 hours after administration of trig/kg, and finally with the analogous p-(2,4 dichlorophenoxy) phenylacetic acid there was severe ulceration 24 hours after administration of 1 g./ kg.

o-Phenoxyphenylacetic acid is therefore much less ulcerogenic than the m and p-isomers. This property is retained in the substituted compounds, which also display anti-inflammatory activity.

Several compounds, e.g. 2-(2,4-dichlorophenoxy) phenylacetic acid and 2 (2,4-dichloro 3,5 dimethylphenoxy) phenylacetic acid, in addition to anti-inflammatory activity possess antipyretic activity. The former compound also has analgesic activity, and exerts an anti-oedematous effect in adrenalectomized rats.

The pharmaceutically acceptable diluents or carriers which may be admixed with the active compound to town the compositions of this inventions are well known. The compositions may be in a form suitable for oral, topical or parenteral use but the preferred method of administration is orally. Such oral compositions may take the form of capsules, tablets, lozenges or granules or liquid preparations such as elixirs, syrups or suspensions. The oral compositions, whether in the form of liquid or solids, may also incorporate flavouring agents, colouring matter, disintegrating agents, tabletting aids and other diluents as required.

Tablets or capsules for oral administration contain from 25 to 500 mg. of a compound according to the invention as active ingredient. A preferred tablet or capsule contains from 100 to 500 mg. of 2 (2,4 dichlorophenoxy)phenylacetic acid, 2 (2,4 dichloro 3,5 dimethylphenoxy)phenylacetic acid, 2-(2 chloro 4 ethylphenoxy)- 5 methylphenylacetic acid, 2 (2 methoxy 4 chlorophenoxy) 5 methylphenylacetic acid, or 2 (2 chloro 4 tert butylphenoxy) 5 methyl phenylacetic acid. A suitable oral daily dose of these preferred compounds for the relief of inflammatory states in human beings, would be from 250 mg. to 3 g. of the active ingredient.

The compounds of the invention may also be incorporated into novel therapeutic compositions with other known therapeutically active compounds such as, for example, codeine. Examples of the formulation and preparation of tablets and capsules for oral administration are set out below:

Tablet An intimate mixture was prepared of equal weights of 2 (2,4 dichlorophenoxy)phenylacetic acid and a tablet base comprising starch with the addition of 1% magnesium stearate as a lubricant. The mixture was compressed into tablets containing 100 mg. of 2 (2,4 dichlorophenoxy)phenylacetic acid.

Similarly tablets containing 50 or 200 mg. of 2-(2,4- dichlorophenoxy) phenylacetic acid were prepared.

Capsule I claim:

1. A method for relief of an inflammatory condition which method comprises administering to a subject having such condition a therapeutically effective amount of a compound of the formula:

o A l CHgCOOH wherein R is selected from the group consisting of hydrogen and methyl;

R is selected from the group consisting of chlorine, bromine and methoxy, provided that R is methoxy only when R is selected from the group consisting of chlorine at position 4 and bromine at position 4;

R is selected from the group consisting of chlorine at position 4, bromine at position 4, chlorine at position 5, bromine at position 5, alkyl of 1 to 6 carbon atoms at position 4, trifiuoromethyl at position 5 and methyl at position 6;

and n is 0, 1 or 2.

2. A method for relief of an inflammatory condition which method comprises administering orally to a subject having such condition a therapeutically effective amount of a compound of the formula:

wherein R is selected from the group consisting of hydrogen and methyl;

R is chlorine;

R is selected from the group consisting of chlorine at position 4, chlorine at position 5, alkyl of from 1 to 6 carbon atoms at position 4, trifluoromethyl at position and methyl at position 6;

and n is 0, 1 or 2.

3. A method as claimed in Claim 2 wherein the compound of the formula is administered in the amount of from 250 mg. to 3 g. per day.

4. A method as claimed in Claim 2 wherein the compound of the formula is 2-(2,4-dichlorophenoxy)-phenylacetic acid.

5. A method as claimed in Claim 2 wherein the compound of the formula is 2-(2-chloro-4-ethylphenoxy)-5- methylphenylacetic acid. -I

6. A method as claimed in Claim 2 wherein the com pound of the formula is 2-(2-chloro-4-ethylphenoxy)- phenylacetic acid.

7. A method as claimed in Claim 2 wherein the compound of the formula is 2-(2-chloro-4-sec-butylphenoxy)- S-methylphenylacetic acid.

8. A method as claimed in Claim 1 wherein the compound of the formula is 2-(2-methoxy-4-chlorophenoxy)- S-methylphenylacetic acid.

9. A pharmaceutical composition for the treatment of inflammatory conditions which comprises an effective anti-inflammatory amount of a compound of the formula:

4 6 In (CI'IZOn B A 2 I I CHQCOOH R is selected from the group consisting of chlorine at position 4, bromine at position 4, chlorine at position 5, bromine at position 5, alkyl of 1 to 6 carbon atoms at position 4, trifluoromethyl at position 5 and methyl at position 6; and n is 0, 1 or 2; and a pharmaceutically acceptable diluent or carrier.

10. A pharmaceutical composition for oral administration in the treatment of inflammatory conditions which comprises an effective anti-inflammatory amount of a compound of the formula:

I CHzCOOH wherein R is selected from the group consisting of hydrogen and methyl;

R is chlorine;

R is selected from the group consisting of chlorine at position 4, chlorine at position 5, alkyl of from 1 to 6 carbon atoms at position 4, trifluoromethyl at position 5 and methyl at position 6;

and n is 0, l or 2; and a pharmaceutically acceptable, diluent or carrier.

11. A pharmaceutical composition as claimed in Claim 10 in tablet or capsule form wherein each tablet or capsule contains from about 25 to 500 mg. of the compound of the formula.

12. A pharmaceutical composition as claimed in Claim 10 which consists essentially of 2-(2,4-dichlorophenoxy)- phenylacetic acid and said diluent or carrier.

13. A pharmaceutical composition as claimed in Claim 10 which consists essentially of 2-(2-chloro-4-ethylphenoxy)-5-methylphenylacetic acid and said diluent or carrier.

14. A pharmaceutical composition as claimed in Claim 10 which consists essentially of 2-(2-chloro-4-ethylphenoxy)-phenylacetic acid and said diluent or carrier.

15. A pharmaceutical composition as claimed in Claim 10 which consists essentially of 2-(2-chloro-4-sec-butylphenoxy)-5-methylphenylacetic acid and said diluent or carrier.

16. A pharmaceutical composition as claimed in Claim 10 which consists essentially of 2-(2-methoxy-4-chlorophenoxy)-5-methylphenylacetic acid and said diluent or carrier.

orally ingestible No references cited.

STANLEY I. FRIEDMAN, Primary Examiner UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION -3J845,2l5 Datfli October- 29, 197% Invmfiwr(s) wwTmn Ppmwsm GHHFRFV It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, after line 9, insert Claims priority, Application Great Britain, April 14, 1970, l7,832/70; line 41, change "ulcertation" to -ulceration-; line 51, change "ulcerongenic" to -ulcerogenic-;

Column 2, line 51, change the formula to read 2-(2-chloro- 4-alkyl (C to C phenoxy) phenylacetic--; lines 53 and 54, change the formula to read 2-(2,4 dichlorosubstituted phenoxy) phenylacetic-.

Column 3, line 5, change "persence" to -presence---;

.line 32, change the formula to read 2-(2-chloro-5- trifluoromethylphenoxy)5- methylphenylline 43, change'bo O(0Et to CO(OEt) line 47, change "ArCHMe(CO Et) to ArCMe(CO Et) line 51, change "ArCHMe(CO H) to -ArCMe(CO H) Column 6, line 55, change "5-n-pentylphenol" to 4-npentylphenol-.

Column 9, delete lines 47 and 48.

Signed and sealed this 24th day of June 1975.

(SEAL) xtte C. MARSHALL DANN RUTH C. MASON Commissioner of Patents attesting O ficsr and Trademarks FORM Po-1os0 (10-69) USCOMM-DC 8O376-P69 ILSI GOVERNMENT PRINTING OFFICE: l9! 0-366-334- 

1. A METHOD FOR RELIEF OF AN INFLAMMATORY CONDITION WHICH METHOD COMPRISES ADMINISTERING TO A SUBJECT HAVING SUCH CONDITION F THERAPEUTICALLY EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA: 